Cardiovascular disease (CVD) is the leading cause of death and disability in women. Psychosocial stress increases CVD and CVD risk factors in women and female cynomolgus monkeys, and leads to depression and ovarian dysfunction, which are especially important CVD risk factors for women. Environmental stimuli that affect CV health are initially processed by the brain. Increasingly, the brain is understood to be nutrition- sensitive, biochemically plastic, and capable of modulating the function of downstream stress-sensitive systems. Importantly, most of the data demonstrating stress effects on CVD have been derived from subjects consuming a Western diet, a metabolic stressor which may exacerbate the effects of psychosocial stress on the system. In contrast, prudent Mediterranean-like diets have been associated with decreased risk of depression, infertility, traditional CVD risk factors, and CVD. Emerging experimental data suggest that certain characteristics of a Western (high-fat) diet exacerbate physiologic and behavioral stress responses, reflecting the associations linking Western diet consumption with perceived stress in population studies. Thus, psychosocial stress effects on CVD or atherosclerosis risk may not be simply main effects of stress; they may reflect diet-exacerbated stress reactivity. A key factor at the interface of stress, diet, and CVD risk is inflammation. Circulating monocytes are important mediators of inflammation, and are precursor cells for macrophages - central players in atherogenesis and CVD. Monocytes are sensitive to dietary and stress effects, and may provide a key nexus for understanding stress effects as well as novel targets for therapies. Here we propose to test the hypotheses that diet and stress interact to have a long term impact on cardiovascular health by epigenetically reprogramming monocyte phenotypes relevant to CVD risk, and that the consumption of a Mediterranean diet will mitigate these effects of stress. These outcomes will be evaluated in the context of transcriptomic and epigenomic phenotypes of peripheral blood monocytes and cardiovascular disease in female nonhuman primates. We will use our well-characterized female cynomolgus macaque model, which consume carefully controlled diets and are physiologically and genetically very similar to people. This study will be cost- effective because we can take advantage of the resources from an existing funded project (R01 HL 87103-06). If successful, the proposed study will provide mechanistic insights into a cost-effective intervention on psychological stress with the promise of widespread efficacy for millions of individuals at risk for CVD.